HIV infection is associated with persistent, aberrant immune activation that supports viral replication and contributes to the progressive immune dysfunction associated with HIV disease progression. Chronic immune activation, whether induced by persistent foreign antigens or loss of self-tolerance, activates and expands host-mediated immunosuppressive mechanisms that prevent immune-mediated damage to the host. In addition to limiting autoimmunity, several of these mechanisms suppress immune responses directed against foreign antigens and affect the ability of the host to eliminate or control certain tumors and bacterial, parasitic and viral infections. These mechanisms include cells with immunosuppressive activity, negative regulatory surface molecules, and anti-inflammatory/immunosuppressive soluble factors. During conditions of significant lymphocyte expansion, such as immune reconstitution following disease (such as HIV-infection) or chemically-mediated depletion, the potential for autoimmunity increases. We recently demonstrated that common gamma chain (gC) cytokines, IL-2, IL-7, IL-15 and IL-21, directly upregulate the expression of the negative regulatory molecule PD-1 and its'ligands, PD-L1 and PD-L2, in T cells and monocytes. In support of these observations, significant increases in the population of PD-1+ T cells and PD-L1+ and PD-L2+ monocytes were observed in PBMCs of HIV+ individuals following IL-2 administration in vivo. PD-1 engagement failed to inhibit gC cytokine-driven T cell proliferation, survival or signaling events;however, the PD-1 axis induced by gC cytokines suppressed proliferation and function of T cells upon triggering the TCR (antigen). These gC cytokines play an important role supporting T cell expansion, survival and function and are currently being used as immunotherapy or vaccine adjuvants. Our data suggest that the PD-1 axis serves to control autoimmunity during cytokine-driven immune reconstitution. We have also investigated the role of the PD-1 axis in the context of HIV disease. We find that neutralization of PD-L1, but not PD-L2, significantly enhances HIV-specific T cell proliferative responses. In contrast, PD-L2, but not PD-L1, plays a modest role in apoptosis of PD-1+ T cells. The enhancing effects of PD-L1 PD-L2 neutralization on cytokine production by HIV-specific T cells relies on T cell expansion and survival. These data point to potentially differential roles/mechanisms of endogenous PD-L1 and PD-L2 in the suppression of HIV-specific T cell responses. It remains to be established whether the quality of HIV-specific T cell function can be enhanced by blocking PD-1 and PD-1 ligand interactions. We have previously demonstrated that the ability of immunosuppressive CD25+ regulator T(reg) cells to suppress HIV-specific proliferation and CTL activity differ, and that HIV disease progression is associated with dysfunction of or reduced sensitivity to mechanisms involved in suppressing proliferation, but not CTL activity. We now find that the overall effect of the immunosuppressive cytokines, TGF-b and IL-10, also varies with disease status. In viremic individuals (with persistent virus) HIV-specific CD8+ T cells are highly differentiated, are prone to cell death and undergo high rates of turn over. In vitro, TGF-b and IL-10 reduce cell death in this population, increase the frequency of CD8+ cells, and ultimately improve HIV-specific responses over time. In contrast, the number and function of HIV-specific CD8+ T cells from individuals with long-term control of HIV in vivo were reduced following exposure to these cytokines. These data point to the potential beneficial effects of immunosuppression in viremic, chronically HIV-infected individuals.